This is a K01 award proposal for Galateia Kazakia, Ph.D; a postdoctoral fellow at the University of California, San Francisco. This K01 award will provide Dr. Kazakia with the support necessary to accomplish the following goals: 1) to become an expert in clinically oriented bone quality imaging research; 2) to develop tools and techniques for in vivo imaging of cortical bone micro-structure; 3) to conduct a clinical investigation of the incidence, progression, and consequence of cortical marco-porosity in human subjects; 4) to obtain training in clinical research, musculoskeletal diseases and statistical methods; and 5) to develop an independent research career. To achieve these goals, Dr. Kazakia has assembled a mentoring team composed of: Sharmila Majumdar, Ph.D (primary mentor), Director of UCSF Musculoskeletal Quantitative Imaging Research Group and expert in development and application of advanced imaging modalities to the musculoskeletal system; Deborah Sellmeyer, M.D., who as Director of UCSF Center for Osteoporosis has extensive experience in clinical osteoporosis research; Thomas Lang, Ph.D, an expert in QCT image acquisition and processing; Ying Lu, Ph.D., Director of the UCSF Biostatistics in Radiology group; and Nancy Lane, M.D., Professor of Medicine and Rheumatology at the UC Davis Medical Center. With the development of high resolution non-invasive imaging techniques capable of visualizing skeletal micro-structure, evidence of large cortical macro-porosity has been found in osteopenic populations. While the biomechanical impact of this macro-porosity is likely to be great, reports of its incidence are anecdotal, its morphology is not characterized, and its etiology is unknown. The objective of this proposal is to develop tools for the structural characterization of cortical macro-porosity in high resolution peripheral QCT (HR-pQCT) data, and to investigate the incidence, progression, and consequence of cortical macro-porosity in human subjects. In Aim 1, image processing tools and quantitative 3D structural measures will be developed to characterize cortical macro-porosity in HR-pQCT images. In Aim 2, macro-porosity measures in healthy and osteopenic subjects will be quantified and compared. In Aim 3, a cross-sectional study will be performed to determine whether macro-porosity parameters can discriminate women with fragility fracture from controls. This research will form the basis for a prospective fracture risk assessment study, to be proposed in an R01 grant application during the final stage of this K01 training period.